The present invention relates to improving the treatment of chronic illness in humans and animals. In particular, the invention relates to kits and methods that improve chronic treatments using data obtained from individual random crossover (n=1 or single patient) double-blind studies.
Inappropriate prescribing of potent and potentially dangerous drugs is a problem of staggering dimensions. Nonetheless, no commercial solution has been advanced to ensure appropriate treatment. Presently, doctors prescribe medications which have approved indications determined by large clinical trials. Drug manufacturers also demonstrate a product""s safety and effectiveness using well controlled clinical studies in populations likely to require its use (e.g. hypertensive patients for antihypertensive drugs). Relatively small numbers of highly selected subjects are utilized. Too often, these studies do not accurately predict the safety and efficacy of a medication for individuals actually treated in practice.
Thus, prescribers are at a disadvantage because a highly selected, often homogeneous group of patients is actually studied for marketing approval. The prescribing physician often cannot distinguish which drugs are safe and effective for his/her heterogeneous collection of individual patients. Even in homogeneous groups of patients, individual variation is usually large when a pharmaceutical company measures a drug""s disposition and activity. Therefore, average results may be poorly suited to the needs of any given individual. It is rarely clear to the prescribing physician how an individual patient might respond to a given medication. This is because all people respond differently, both positively and negatively, based upon individual genetic and environmental factors.
Furthermore, the physician rarely has objective information to help decide between alternative therapies for an individual patient. Although the physician wants unbiased data concerning how a patient responds to a given therapy, such data is almost never available unless the patient is in a drug trial. The physician is almost always required to use subjective xe2x80x9cclinical judgmentxe2x80x9d.
Pharmaceutical manufacturers are also at a disadvantage since they have no means of providing unbiased data for individual patients. Manufacturers rarely receive feedback on how a drug is used in actual practice unless an adverse event is reported. Other organizations often need unbiased information for regulatory, patient care and business purposes. Currently, unreliable retrospective databases, such as government or health maintenance organizations"" epidemiologic databases, are used.
In 1985, investigators proposed a single-patient drug trial as a possible solution. Using this study design, a patient is treated with a medication and a placebo in a double-blind randomized manner (n=1 or single patient drug trial). This approach permits assessment of whether a medication regimen is appropriate for an individual patient in terms of medical benefit and harm. This approach eliminates patient/physician bias by making the medication and placebo look and/or taste the same. Thus, a toxic or ineffective treatment can be avoided by using objective criteria and new treatment regimens can be pursued for well documented reasons and similarly tested, if needed. This alternative is purely subjective trial and error.
The single-patient method, however, has significant shortcomings. It has failed to provide validated results. There was no appreciation that the data obtained from the single trial should be compared against a database compiled from similarly affected and tested patients. Moreover, no guidance was provided concerning therapeutic alternatives based upon a database comprised of earlier patient experience during single-patient trials.
No commercial products are believed to be available which allow objective and definitive measurement of individual patient compatibility with drug treatment compared to placebo or a therapeutic alternative. The present invention addresses this need.
It is therefore an object of the present invention to develop methods and kits which can assess the appropriateness of specific drug treatment in individuals, particularly those suffering from chronic illnesses.
It is a further object to provide methods and kits for testing therapeutic alternatives for drug treatments in individuals.
Thus, in one aspect, the invention includes a method of treating human and veterinary illnesses. The method includes:
a) providing to a pool of humans or animals in need of such treatment a test kit containing:
i) a supply of a drug indicated or proposed for the treatment of an illness;
ii) a supply of a placebo substantially identical in appearance to the drug,
iii) a questionnaire designed to elicit from each pool member to be treated information concerning the actual usage, safety, efficacy and desirability of the selected treatment;
b) administering the drug and placebo to each member of the pool according to a random, double-blind schedule;
c) assembling a database from the pool based on the answers provided from the individual questionnaire;
d) revealing the random schedule and comparing the data obtained from known drug and placebo treatment periods;
e) providing a test kit containing the same materials as set forth in a) to a human or animal also in need of such treatment to obtain a separate or second set of data concerning the safety, efficacy and desirability of said treatment;
f) administering the drug and placebo to the human or animal according to a random, double-blind schedule;
g) assembling the second or separate database based on the answers provided to the questionnaire;
h) revealing the random schedule to uncover drug and placebo treatment periods;
i) comparing the data obtained from the pool with that obtained from the single human trial to determine an optimal treatment of the human or animal with the drug; and
j) administering to the human or animal a treatment consistent with the optimal treatment.
The new dosing regimen for optimal therapeutic effect and quality of life can also be retested, if and when deemed appropriate, by the clinician and/or patient.
The method is suitable for evaluating and validating any prescription or non-prescription treatment regimen or medication for individuals as well as demographic groups. Using this method, one can periodically obtain further outcome information on tested individuals.
Other aspects of the invention include a method and kit for determining therapeutic alternatives and verifying generic equivalence of known medications. These methods include:
a) providing to a human or animal a test kit containing:
i) a supply of a drug indicated for the treatment of an illness;
ii) a supply of a therapeutic alternative or generic equivalent candidate substantially identical in appearance to the drug,
iii) a questionnaire designed to elicit from the human or animal information concerning the safety, efficacy and desirability of the treatment for the human or animal;
b) administering the drug and therapeutic alternative to the human or an animal according to a random, double-blind schedule;
c) assembling a database by eliciting from the human or animal caretaker answers to the questionnaire; and
d) revealing the random arrangement schedule to determine the relative effectiveness of the therapeutic alternatives in the human or animal by comparing the data obtained from knowing drug and alternative treatment periods.
There are several advantages associated with the present invention. For example, patients benefit by the assurance of treatment with appropriate drug and dosing regimen. The method is particularly useful before committing a patient to a long term drug treatment regimen. Documented evidence of the benefit is provided. Unnecessary side effects and expense can be avoided.
Government agencies could also benefit by the availability of a dynamic database on drug efficacy and safety in individuals. The inventive method also provides an alternative means for approving new drugs. In this aspect, the new drug or therapeutic alternative could be tested according to the methods described herein against a placebo or a known effective agent and/or indicated therapy in individuals and/or a pool of suitable candidates. This is a particular advantage to the pharmaceutical industry and affords a method to validate the therapeutic equivalence of generic drugs as well as non-generic therapeutic alternatives.
Insurers and managed care organizations could benefit by having a reliable xe2x80x9csecond opinionxe2x80x9d to help avoid expensive, prolonged, unneeded, or toxic treatments, and promote utilization of safe and effective therapies.
The present invention provides advances over prior art single patient drug trials (n=1) by optimizing treatment for the individual. Unlike (n=1) studies, which by definition, had a sample size of one, the invention includes comparing the data obtained from the individual with a database accumulated for an entire tested population, referred to as a pool herein. This results in the opportunity to create a prospective, frequently updated epidemiological database which has value not only for regulatory approvals or post-marketing surveillance of drug safety and efficacy, but also for optimizing outcome in individuals as well.
The present invention includes a method and kit for determining the appropriate treatment of an illness. The method includes:
a) providing to a pool of humans or animals in need of such treatment a test kit containing:
i) a supply of a drug indicated for the treatment of an illness;
ii) a supply of a placebo substantially identical in appearance to the indicated drug,
iii) a questionnaire designed to elicit from each member of the pool information concerning the safety, efficacy and desirability of the selected treatment;
b) administering the drug and placebo to each member of the pool according to a random, double-blind schedule;
c) assembling a database by eliciting from the pool data from the answers to the questionnaire;
d) revealing the random schedule to uncover drug and placebo treatment periods;
e) providing a test kit containing the same materials as set forth in a) to a human or animal also in need of such treatment to obtain a second or separate set of data concerning the safety, efficacy and desirability of the treatment;
f) administering the drug and placebo to the human or animal according to a random, double-blind schedule;
g) assembling a separate database by eliciting from the human or animal caretaker answers to the questionnaire;
h) revealing the random schedule and comparing the data obtained as a result of known active(s) and placebo(s) treatment periods;
i) comparing the results obtained from the first set of data obtained from the pool with the second set of data obtained from the single trial to determine an optimal treatment of the human or animal with the drug; and
j) administering to the human or animal a treatment consistent with the optimal treatment, based upon individual and group outcome. Results from the individual, and post-study follow-up data can also be added to the general database.
Even after the data obtained from the questionnaires is obtained, the caregiver can continue to periodically use the same kit or other kits with different test articles, analyzing the further results for relative scoring, or monitoring further treatment based on physician and patient awareness of study results.
For purposes of description of the present invention, certain terms are described below. Generally, however, the terms have the commonly understood meaning known to those of ordinary skill in the art.
Drug shall mean a medicament, biologically active ingredient, or pharmaceutical dosage form containing an active ingredient effective for one or more medical conditions. The drug may be in any known dosage form including tablets, capsules, solutions, elixirs, ointments, creams, etc.
Placebo shall mean an inert or inactive dosage form having an appearance and/or other organoleptic/sensory characteristics substantially identical to an active drug.
Treatment or treating includes administering a generally recognized effective amount of a drug for the purpose of alleviating or curing a disease or deficiency.
Optimal or optimizing treatment means a treatment regimen which has been adjusted or validated in view of a comparison of objective data relating to one or more treatment periods with one or more active medicament(s) and one or more of placebo, therapeutic alternative or generic equivalent. This is further adjusted by consideration of outcomes from similarly tested populations. Treatments consistent with optimal treatment are those which adjust the time, manner or amount of a drug or therapy for maximum effect, or even cease to treat with the drug or therapy.
Supply means a quantity sufficient for completing a statistically valid evaluation of a treatment method in an individual.
Therapeutic alternative means a medicament having a non-identical chemical composition from a known medicament but achieves substantially the same bio-effect in an individual.
A generic drug or medicament means a substantially identical active ingredient to a known composition.
Chronic shall mean treatment for a condition which lasts an indefinite period of time. Treatments amounting to more than a single course of therapy. Maintenance dosing regimens are also contemplated.
Prolonged therapy shall mean therapy wherein doses are administered to a patient over a period of greater than 10 days, including multiple episodes or recurrences of shorter duration. For example, a psoriasis or herpes episode may require treatments of less than 10 days but the condition requires prolonged therapy.
The term xe2x80x9cdouble-blindxe2x80x9d shall be consistent with its known meaning and include known techniques such as single or multiple crossover techniques well known to those of ordinary skill. Double-blind means that the patient, or caretaker if appropriate, and care-giver do not know exactly when the drug, alternative or placebo is given.
For purposes of description, the method and kit can be described as a Single-Patient Assessment System (SPAS). The SPAS provides a health care practitioner with objective data based on each individual patient""s unique circumstances, allowing therapy to be tailored to individual needs. In addition, the unique method generates prospective, directly measured epidemiologic safety and efficacy data. Pharmaceutical companies can use this data to gain regulatory approval for new indications or to differentiate efficacy and/or safety benefits between competing products, and to provide pharmaceutical manufacturers, government and health care organizations with demographic and usage data on products. Importantly, the database can also be used by government agencies to monitor the safety and efficacy of drugs in the marketplace. Using statistical sub-group analyses, data can be generated to define the level of efficacy or safety in various special populations. For example, data can be segregated by age, disease severity, onset of illness, and concurrent medications.
One preferred embodiment of the invention includes the use of the SPAS to demonstrate the effectiveness of the specific treatment for the specific individual, that is, to document the probability that the medication is beneficial without causing unacceptable side effects. Specifically, the system consists of a clinical evaluation kit which generates definitive guidance regarding the safety and efficacy of drug therapy in each individual patient. The kit contains a full supply of medication to be evaluated and/or placebo, as well as all instructions and evaluation instruments for professionals and patients.
A key feature of the present invention is the double-blind manner in which the drug or placebo, or alternative, is being administered. Both the patient and the physician are unaware of what any dose given is. This is essential since placebo and active drug are randomly administered and look identical to eliminate any bias in the results. A neutral observer/administrator keeps the record of the random arrangement, assembles the data from completed questionnaires and after completion of the test, xe2x80x9cbreaks the codexe2x80x9d to reveal the schedule of drug and/or placebo doses and analyze the accumulated data. The physician and/or patient is/are then given a report on the efficacy and safety of the drug in question. The report has the feature of being validated because the data obtained from the single patient is compared to data obtained from a pool of individuals who also required treatment, were given the kit, and were followed up when appropriate for efficacy and safety data post-testing. This can be used for guidance in directing further therapy, referred to herein as a treatment consistent with optimal treatment. The results of individual assessments can be monitored, with subsequent outcomes added to the database. Data generated from a pool of individual studies can then form the basis of a large population database reporting system which serves to further validate the effectiveness of any singular trial or single indication for a medication.
The SPAS includes means for providing the drug(s), placebo(s) and questionnaire(s) such as a kit. The kit may contain convenient pocket-sized cards which contain a sufficient supply of active drug(s) and placebo(s) or therapeutic alternative(s) in blister packages labeled with the day and time of dosing. For example, a kit may contain eight cards for a required trial, each corresponding to one of eight weeks of treatment, and contain daily regimens of either active drug or placebo, at carefully selected times during the eight week period. The tablets in the card are xe2x80x9cblindedxe2x80x9d so that neither the patient nor the physician is aware of which preparation is received at any given time. In an emergency, the random arrangement can be broken. Under normal circumstances, the code will not be made available, thereby eliminating any bias in the results.
At various times during the evaluation, the program prompts the clinician, patient and/or guardian/observer to fill out questionnaires or other instruments which assess numerous efficacy and safety variables relating to improvements in physical and behavioral symptoms.
At the end of the study, all drug cards (used and unused) as well as questionnaires are returned and the results are evaluated. These results are provided to the physician and patient so that guidance can be provided regarding the safety and efficacy of the treatment for the tested patient. These data can also be added to a master database along with other data on family history, demographics, socioeconomic factors, and post-study outcome.
Numerous drugs and indications can be evaluated using the methods of the present invention. Suitable illness for which the present invention can be used include, without limitation, asthma, cancer, epilepsy, schizophrenia, minimal brain dysfunction, mania, depression, anxiety, hypertension, angina, congestive heart failure, cardiac arrhythmias, pain, etc.
Suitable drugs for evaluation include, without limitation, those agents currently approved for the above-identified conditions as well as agents awaiting approval and new chemical entities. For example, the drug can be selected from anti-asthmatic agents, dental agents, anti-epileptic agents, anti-psychotic agents, anti-depressants, cardiovascular agents, respiratory agents, antihypertensive agents, diabetic agents, steroidal and non-steroidal anti-inflammatory agents, opiates, narcotic and non-narcotic analgesics, hematologic agents, musculoskeletal agents, anti-anxiety agents, gastro-intestinal agents, dermatologic agents, and anti-allergy medications. Other categories not specifically mentioned are intended as well. Particular agents well suited for the methods of the present invention include methylphenidate, estrogen-containing agents, anti-asthmatic agents, cardioactive agents, and antidepressant agents.
Oral, mucous membrane, nasal, surgical, musculoskeletal, central nervous system, urinary tract, psychiatry, nephrology, neurology, genital, podiatry, chiropractic, pediatric, geriatric, acupuncture, allopathy, homeopathy and osteopathy treatments can be also be evaluated.
It is to be understood that where veterinary treatments and therapies are to be tested,the questionnaires and assembly of data are provided by human caretaker/observers. Furthermore, it is to be understood that the term questionnaire refers generally to a means by which information can be related back to the evaluator. The results need not be transmitted in written form. Computer-assisted data recording and communication devices and measuring instruments can also be part of the database assembly step.
An additional list of uses includes:
1) Socially/medically controversial uses for drugs where the relationship of risk to benefit is not well defined. For example, depression, asthma, and hyperkinetic behavior are representative chronic ailments which can be evaluated and available treatments can be challenged.
2) Chronic disease states which may or may not benefit from long term drug treatment. Controlled drug xe2x80x9cholidaysxe2x80x9d are needed to test if chronic medication is paradoxically compromising quality-of-life, has no effect or is helping and should be continued. Category examples include cardiovascular disease, hypertension, and arthritis.
3) xe2x80x9cCompassionatexe2x80x9d Investigational New Drug Application (IND) drug trials for drugs/indications which command a fast track regulatory approval process, such as drugs used for treatment of AIDS. Pharmaceutical companies can pursue early xe2x80x9ccompassionatexe2x80x9d marketing in the form of a drug trial in subjects who urgently need the new therapy. Also, early New Drug Application (NDA) approval can be pursued by carefully controlling drug use, investigational documentation and data analysis in the community-practice setting. These regulatory strategies can be economically and effectively accomplished using Single-Patient Assessment Systems (SPAS).
4) Clinical comparison between innovator and generic drugs. Single-Patient Assessment Systems (SPAS) can be used to validate or invalidate use of generic drugs for regulatory or marketing purposes. Single-Patient Assessment Systems (SPAS) can be used to gain approval for generic drugs which are not readily approved by traditional bioequivalence testing. The method and kit can offer a consumer assurance of a successful switch from the innovator""s product, and assurance that the drug actually improves his or her quality-of-life.
Another example of the method and kit is for evaluation of new or generic drugs, or evaluating new indications for marketed drugs or therapeutic equivalents. This includes determining a therapeutic alternative for a known drug for an individual requiring treatment. This aspect includes:
a) providing a human or animal a test kit containing:
i) a supply of a drug indicated for the treatment of an illness;
ii) a supply of a therapeutic alternative substantially identical in appearance to said drug,
iii) a questionnaire designed to elicit from the person or animal caretaker information concerning the safety, efficacy and desirability of the treatment;
b) administering the drug and therapeutic alternative to the person or animal according to a random, double-blind schedule;
c) assembling a database from the answers to the questionnaire; and
d) revealing the random arrangement schedule to determine the effectiveness of the therapeutic alternative by comparing the results obtained from known drug and alternative treatment periods.
This method may also include additional steps which serve to validate the data obtained in any single trial. The steps are:
e) providing the same type of test kit to a pool of humans or animals in need of such treatment and obtaining from the pool a second set of data including post-study following information where appropriate, concerning the safety, efficacy and desirability of the treatment with the drug and therapeutic alternative; and
f) comparing the data obtained from an individual with that obtained from the pool to verify the effectiveness of the therapeutic alternative.
The method described herein also contemplates that the therapeutic alternative is a generic equivalent for the drug and/or the same drug but at a different dosage or even same dosage.
The present invention has a myriad of uses. For example, it can be used to test, confirm or verify a particular therapy""s safety and efficacy. It can also provide demographic, marketing, sales or professional usage information. New indications, patterns of use, compliance, therapy relationships to other disease states, relationships between concomitant medications, laboratory result relationships can be uncovered. The kit can be used in regulatory filings, dose titration, placebo controlled, crossover, food effect, dose proportionality, bioavailability, single dose, multiple dose and market research studies. Age effects, socioeconomic effects, sex effects, and disease effects can also be determined. Moreover, the role of heredity, diet, geographic location, demographics, occupation, epidemiology, patient education, drug interactions, dose response, time to onset, dosage individualization, regimen individualization, dose finding, dose ranging, rising dose, dose titration or overdose can be determined.
The kits of the present invention also have value to physicians. Legal documentation concerning rational drug therapy, compliance, monitoring, documentation of decision making, appropriateness of therapy, ease of following instructions for administration of therapy and documentation of safety and efficacy are all achieved by the inventive process. The method gives a reason for patient compliance and drug effects, a mechanism for follow-up of therapy, the ability to ease concerns about safety-efficacy. The ability to use blinded placebo treatment methods and the ability to remove bias from decision making, ease of screening out psychosomatic illness are all provided. The kit can provide drug holidays in blinded manner to foster compliance, make available objective feedback and an unbiased and rational approach to therapy. The kit allows the involvement of all physicians and/or patients in clinical trials, early patient participation in therapy, decreases time for regulatory submissions with less initial use of specialists in clinical trials and less dependence on traditional clinical investigators. All of these features decrease overall medical costs, the costs of new drug development, increases accuracy of diagnoses and potentially decreases malpractice.
The kit and method has value to patients by lessening the fear of inappropriate medicine and providing the feeling that something important is being done. Individualization of therapy for patient, decreased side effects, increased efficacy, decreased risk of treatment, controlled drug holidays are all realized. Patients have the enhanced ability to use new and unapproved treatments when needed with the enhanced ability to participate in clinical trials. The kit decreases overall costs of treatment, eliminates unnecessary therapies and tests, reminds patients when to use drugs, prevents under or overdoses, fosters relationships with clinicians, increases understanding of disease and drug.
Industry will benefit from the invention by having a means to gain early drug approval, a marketing tool, a reduction of clinical trial costs, better clinical trials, larger clinical trial database, broader patient population for clinical trials, ability to conduct well controlled, small scale, initial clinical trials, a means for post-marketing surveillance, as well as a means to document therapeutic bioequivalence.
The kit and method""s value to government is realized by providing a means to remove clinician/company/patient bias in important therapy, protecting the public from inappropriate drug use, decreasing the cost of public health, and lowering the cost of effective clinical assessment of new and existing drugs, more rapidly approving new drugs and indications, providing highly controlled methods to deploy needed but unapproved treatments, and providing new methods for phase I through IV treatment evaluations.
Third party healthcare organizations, insurers and managed care organizations benefit by the assurance of need for expensive and/or potentially dangerous therapies, overall decreased cost of treatment, decreased use of unneeded and/or multiple therapies.
Pharmacists benefit by the availability of new products, enhanced role in patient care, greater interaction with patients and with other health care professionals.